N-((R)-α-methyl-3-methoxybenzyl)-3-(2-chlorobenzene)propanamide

ABSTRACT

A method of making ( R)- N-[1-(3-methoxyphenyl)ethyl]-3-(2-chlorobenzene)propanamine which involves reducing the appropriate amidyl or iminyl precursor with an appropriate reducing agent. The appropriate amidyl or iminyl precursor is made from a synthesis involving the use of ( R)-3-methoxy-α-methylbenzylamine. A method of condensing a nitrile with a primary or secondary amine to form an imine involves the reaction of a nitrile with diisobutylaluminum hydride; and then reacting the resultant compound with a primary or secondary amine to form the imine. The process is especially useful for producing enantiomerically pure chiral imines, and, ultimately, amines. Typical such imines have the formula: ##STR1## wherein R, R 1 , R 2  and R 3  are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, aryl and aralkyl.

This is a division of pending prior application Ser. No. 08/446,491filed on May 22, 1995 which is a division of application Ser. No.08/276,214, filed Jul. 15, 1994 (now U.S. Pat. No. 5,504,253 issued onApr. 2, 1996).

TECHNICAL FIELD

The invention relates to a method for preparing achiral or chiral iminesand/or achiral or chiral amines.

BACKGROUND

As disclosed in Fox et al. "A First Generation Calcimimetic compound(NPS R-568) that acts on the Parathyroid Cell Calcium Receptor: A NovelTherapeutic Approach for Hyperparathyroidism," Journal of Bone andMineral Research, 8: S181, abstract 260 (Suppl. 1, Aug. 1993), compoundssuch as (R)-N-[1-(3-methoxyphenyl)ethyl]-3-(2-chlorobenzene)propanamine(also known asN-[3-(2-chlorophenyl)propyl]-R-α-methyl-3-methoxybenzylamine,(R)-N-(3-methoxyphenylethyl)-3-(2'-chlorophenyl)-1-propanamine or "NPSR-568"), i.e.: ##STR2## have utility in the treatment ofhyperparathyroidism and possibly other bone and mineral relateddisorders and diseases.

A straight-forward chemical synthesis for such compounds would be animprovement in the art.

DISCLOSURE OF THE INVENTION

The invention includes a method of making(R)-N-[1-(3-methoxyphenyl)ethyl]-3-(2-chlorobenzene)propanamine whichinvolves reducing the appropriate amide or imine precursor, i.e.:##STR3## wherein amino is either ##STR4## with an appropriate reducingagent. The appropriate amide or imine precursor will generally be madefrom a synthesis involving the use of (R)-3-methoxy-α-methylbenzylamine.

The invention further relates to a general process for condensing anitrile with a primary or secondary amine to form an imine. The methodinvolves reacting a nitrile with diisobutylaluminum hydride (DIBAL-H),and then reacting the resultant complex with a chosen primary orsecondary amine to form an intermediate imine.

The DIBAL-H embodiment of the inventive process is especially useful forproducing enantiomerically pure chiral imines, and, ultimately, amaines.Typically such imines have the formula: ##STR5## wherein R, R₁, R₂ andR₃ are independently selected from the group consisting of hydrogen,substituted or unsubstituted alkyl, aryl and aralkyl.

After synthesis of the imine, it will typically be reduced to an amineof the formula: ##STR6## wherein R, R₁, R₂ and R₃ are as previouslydefined.

The DIBAL-H mediated condensation of amines with nitriles has broadapplication, affords good yields, and does not require the use of excessamine or nitrile.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of a 200 MHz ¹ H NMR (CDCl₃) of camphorsulfonamidesobtained from reaction of racemic 3-methoxy-α-methylbenzylamine with(+)-10-camphorsulfonyl chloride.

FIG. 2 is a plot of a 200 MHz ¹ H (CDCl₃) of camphorsulfonamide obtainedfrom reaction of (R)-3-methoxy-α-methylbenzylamine with(+)-10-camphorsulfonyl chloride.

FIG. 3 is a plot of a 200 MHz ¹ H NMR (CDCl₃) of camphorsulfonamidesobtained from reaction of 3-methoxy-α-methylbenzylamine with(+)-camphorsulfonyl chloride. The 3-methoxy-α-methylbenzylamine waspreviously isolated as the free base after two recrystallizations with(-)-dibenzoyl tartaric acid.

FIG. 4 is a plot of a 200 MHz ¹ H NMR (CDCl₃) of camphorsulfonamidesobtained from reaction of 3-methoxy-α-methylbenzylamine with (+)-10camphorsulfonyl,chloride. The 3-methoxy-α-methylbenzylamine waspreviously isolated as the free base after two recrystallizations with(+)-dibenzoyl tartaric acid.

FIG. 5 is a plot of a 200 MHz ¹ H NMR (CDCl₃) of camphorsulfonamidesobtained from reaction of 3-methoxybenzylamine with (+)-camphorsulfonylchloride. The 3-methoxy-α-methylbenzylamine was previously isolated asthe free base after one recrystallization with (R)-(-)-mandelic acid.

FIG. 6 is a plot of a 200 MHz ¹ H NMR (CDCl₃) of camphorsulfonamideobtained from reaction of 3-methoxybenzylamine with (+)-camphorsulfonylchloride. The 3-methoxy-α-methylbenzylamine was previously isolated asthe free base after two recrystallizations with (R)-(-)-mandelic acid.

BEST MODE OF THE INVENTION

A preferred method of making(R)-N-[1-(3-methoxyphenyl)-ethyl]-3-(2-chlorobenzene)propanamineinvolves reducingN-(R)-α-methyl-3-methoxybenzyl)-3-(2-chlorobenzene)-propanamine with anappropriate reducing agent. When the compound to be reduced is an amide,the compound's carbonyl group is preferably reduced by reacting thecompound with a borane-tetrahydrofuran complex. When the compound to bereduced is an imine, the compound's iminyl group is preferably reducedby reacting the compound with ethanolic sodium borohydride.

The compound to be reduced is preferably produced by the reaction ofR-3-methoxy-α-methylbenzylamine with either β-2-chlorophenylpropionicacid or 2-(2-chloro)-phenyl-1-ethanenitrile.

Diisobutylaluminum hydride is readily commercially available fromAldrich Chemical Co. of Milwaukee, Wis.

The nitrile and amine (or chiral amine) used in the DIBAL-H embodimentof the process will generally be chosen for their respective constituentR and R_(x) groups. The amine is preferably a primary amine. Preferablythe R_(x) groups will be selected from the group consisting ofsubstituted or unsubstituted phenyl, lower (C1 to C4) alkyl, furanyl,pyrrolyl, and thiophenylo Alternatively, the R_(x) groups can beincorporated into an aromatic ring.

When the amine used in the process is (R)-3-methoxy-α-methylbenzylamine,various methods can be used to obtain it. For instance, Japanese patentapplication 58 41,847, 1983, describes the preparation ofoptically-active 3-methoxy-α-methylbenzylamine by treating the racemicform of the compound with (L)- or (D)-malic acid. Refluxing of 45.3 g ofthe racemic form with (L)-malic acid in 300 ml 10% ethanol/waterprovided 26.5 g of the diastereomer, which upon decomposition with 30%aqueous NaOH in water is described as giving 13 g of the (L) isomer.

Alternatively, and as more thoroughly described herein, a method forresolving the enantiomers of 3-methoxy-α-methylbenzylamine includesrefluxing the compound in an appropriate solvent with mandelic acid. Ithas been determined that the use of mandelic acid is advantageous overother procedures, such as refluxing in an appropriate solvent with malicacid, since it provides significantly better yields. This procedure isuseful for the economical production of large quantities (kilogram andlarger) of the (R) enantiomer of 3-methoxy-α-methylbenzylamine. Inpreferred embodiments, the method involves mixing the mandelic acid withisopropanol prior to refluxing the 3-methoxy-α-methylbenzylamine. Othersolvents include ethanol and methanol.

In the formulae described herein, R is a substituted or unsubstitutedalkyl, aryl, aralkyl, or is a heterocycle. R is preferably aralkyl("Ar").

As used herein, alkyl is preferably a saturated or unsaturated, branchedor unbranched hydrocarbon having one to twenty carbon atoms, e.g.,methyl, ethyl, isopentyl, cycloalkyl, and allyl.

Alkoxy groups will typically have one to four carbon atoms and includegroups such as methoxy and ethoxy.

Aryl, as used herein, is an aromatic hydrocarbon group, preferablyhaving six to ten carbon atoms, such as phenyl or naphthyl orheteroaromatic such as indole and quinoline.

Aralkyl, as used herein, is a substituted or unsubstituted arene grouphaving both aliphatic and aromatic portions), preferably having seven tothirteen carbon atoms, such as benzyl, ethylbenzyl, n-propylbenzyl, orisobutylbenzyl.

A "substitution" with regard to the various R and Ar moieties generallyrelates to substituting a group such as hydroxy, alkoxy, halogen, nitro,or lower alkyl onto an aromatic ring for a hydrogen that would normallybe present. Substitutions can also be made on an alkyl or alkoxy chain.

Halogen, as used herein, generally refers to fluorine, chlorine, bromineor iodine.

In the DIBAL-H embodiment of the synthesis, the nitrile, amine, anddiisobutylaluminum hydride are preferably utilized in equimolar orapproximately equimolar proportions (±10%). They are reacted with oneanother, as more completely described herein, in a preferably organicsolvent such as dichloromethane or toluene. Benzene, heptane, ortetrahydrofuran (THF) may also work.

The resulting imines are generally reduced to the corresponding amines.Reducing agents for use with the process are those which will reduce theimine to an amine, but will not otherwise alter the chemical structureof the compound (e.g. ethanolic sodium cyanoborohydride or ethanolicsodium borohydride).

While not intending to be bound by any one theory relating to theDIBAL-H aspect of the invention, the following may help explain theexcellent results obtained from the invention: A nitrile of the formula:

    R--CN,                                                     (I)

is reacted with:

    diisobutylaluminum hydride (DIBAL-H),                      (II)

and is believed to form an intermediate imine-aluminum complex: ##STR7##This complex is reacted with a chiral amine of the formula: ##STR8## toyield an aminal complex: ##STR9## Elimination then affords the chiralimine: ##STR10## If desired, this imine (V) can be reduced (e.g. by theaddition of ethanolic sodium borohydride) to yield the optically pureamine: (VII) ##STR11##

The invention is further described by reference to the followingillustrative EXAMPLES.

EXAMPLES Example I

A. Synthesis of Racemic 3-methoxy-α-methylbenzylamine

An efficient synthesis of the title compound was developed from3-methoxyacetophenone by a Leuckart reaction ((1) ammonium formate,reflux; (2) HCl hydrolysis). This procedure may be easily adapted to avery large scale synthesis.

1. N-[((3-Methoxyphenyl)methyl)-α-methyl]formamide

A mixture of 281 g (1.87 moles) of 3-methoxyacetophenone and 352 g(5.558 moles) of ammonium formate was stirred at 180° C. After 24 hours,TLC analysis (1:1 Hex/EtOAc) indicated that the reaction was complete.The solution was poured into water and extracted with methylenechloride. The organic layer was washed once with H₂ O and dried withMgSO₄. The solution was concentrated to afford 292 g (87%) of a darkoil.

2. 3-methoxy-α-methylbenzylamine

A solution of 287 g (1.60 moles) ofN-[((3-Methoxyphenyl)methyl)-α-methyl]formamide and 1400 mL ofconcentrated HCl was stirred at reflux. After 1.5 hours, TLC analysis(85:10:5 EtOAc/MeOH/isopropylamine) indicated the reaction was complete.The solution was concentrated to dryness and the resulting green residuewas recrystallized from acetonitrile to afford a white solid. The solidwas dissolved in water and the pH was raised to 12 with 50% NaOH. Theproduct was extracted with ethyl ether. The organic layer was washedwith saturated NaCl solution and dried with K₃ CO₃. The solution wasconcentrated to afford 188.2 g (78%) of a dark oil. Distillation of 174g of the dark oil at 760 mm Hg afforded 140 g of a clear liquid, bp 180°C.

3. Analytical Method

To determine enantiomeric purity, an analytical method was required.Because the optical rotation of the pure (R) enantiomer was determinedto be only +3.8° (C=1 in 2N HCl), it was determined that opticalrotation measurements would be insufficient for measuring enantiomericexcess. An NMR derivatization analysis was developed. In this procedurea sample of 3-methoxy-α-methylbenzylamine was reacted with(+)-10-camphorsulfonyl chloride in pyridine. The resultingdiastereomeric camphorsulfonamides were then analyzed by proton NMR.Alternatively, an HPLC method may be adapted for use with the invention.

The NMR spectrum of the diastereomeric camphorsulfonamides obtained fromracemic 3-methoxy-α-methylbenzylamine is shown in FIG. 1. When comparedwith the NMR spectrum of diastereomerically-pure(R)-1-(+)-camphorsulfonamide, it is clear that a number of signals arediagnostic for each enantiomer; including the sulfonamide NH signals (δ5.55 or 6.25 ppm), the camphor CH₃ groups (δ 0.48, 0.80, 0.88 and 1.0ppm) and the OCH₃ signals (δ 3.78 and 3.82 ppm).

This NMR analysis is useful in terms of resolution method development.Any synthetic batches, however, may be analyzed by HPLC for the precisedeterminations required.

B. Resolution

The procedure of JP 58 41,847 for the resolution of(±3-methoxy-α-methylbenzylamine with (L)- malic acid in ethanol--waterwas repeated using seeds generated as subsequently described.Crystallization is extremely slow and mass recovery is low. This saltwas not further pursued because of the success obtained with mandelicacid, as hereinafter discussed.

Prior to experiments with malic and mandelic acids, significant effortswere first directed to the use of tartaric acid as a resolving agent.The pure (R) enantiomer of 3-methoxy-α-methylbenzylamine readilycrystallized with natural tartaric acid from methanol. Unfortunately,even at high dilution, solutions of racemic3-methoxy-α-methylbenzylamine yielded crystals too readily. Even whenseeded with diastereomerically-pure seeds, the solutions would "set up",trapping large quantities of solvent in a thick lattice. For example,when 20 g of (±) 3-methoxy-α-methylbenzylamine was combined with 20 g of(+)-tartaric acid in 700 mL of hot ethanol, the solution set up as itslowly cooled to room temperature. It became clear, based upon the highmass recovery of the resultant free base and its low or nonexistentoptical rotation values, that tartaric acid was not useful.

Attention was next focused on (-)-dibenzoyl tartaric acid ((-)-bET). Onmixing racemic 3-methoxy-α-methylbenzylamine with one equivalent of(-)-DBT in methanol, a granular precipitate immediately developed. Thiswas in contrast to the thick lattice that resulted from tartaric acid.Recrystallization of the (-)-DBT salt obtained from (±)3-methoxy-α-methylbenzylamine yielded slow plate formation. Two factorswere disappointing about (-)-DBT, however. First, mass recovery was notgood. Second, after two recrystallizations from methanol, it wasapparent by NMR analysis of the derived (+)-camphorsulfonamide (FIG. 3)and optical rotation [α]_(D) =-1.0° (c=1.0 in 2N HCl) that3-methoxy-α-methylbenzylamine was enantiomerically enhanced in theundesired direction.

1.5 g of (R) 3-methoxy-α-methylbenzylamine was used, in part, togenerate seed crystals as the salt of a number of acidic resolvingagents. The following resolving agents were added (one equivalent) to amethanolic solution of (R) 3-methoxy-α-methylbenzylamine:(+)-10-camphorsulfonic acid; (-)-10-camphorsulfonic acid; (L)-malicacid; (D)-malic acid; (-)-mandelic acid; (+)-mandelic acid;(+)-dibenzoyl tartaric acid; (R)-(-)-1,1'-binaphthyl-2,2-diylhydrogenphosphate; and, (S)-(+)-1,1'-binaphthyl-2,2-diylhydrogen phosphate. Onlythe solution containing (+)-DBT readily crystallized at thisconcentration in methanol. After slight evaporation, crystals were alsoobtained of the (-)-mandelic acid salt. The (+)-mandelate did not yieldcrystals until evaporation of the methanol was nearly completed.

When (+)-DBT was used as the resolving agent and the solution seededwith diastereomerically-pure crystals, the results were very promising.FIG. 4 shows the NMR spectrum obtained from the camphorsulfonamide aftertwo recrystallizations. This material is a mixture of the twoenantiomers of 1, greater than a 3:1 ratio in the desired sense.

Although the results with (+)-DBT as a resolving agent were promising,even better was the use of (-)-mandelic acid. One crystallization (on a10 game scale) with hot isopropanol with seeding afforded diastereomericsalt containing 3-methoxy-α-methylbenzylamine that was nearlyenantiomerically pure (see FIG. 5). Furthermore, mass recovery was goodon this initial attempt, yielding 70% of theory. A second batch of (±)3-methoxy-α-methylbenzylamine was prepared to repeat this resolution ona slightly larger scale.

C. (R)-3-methoxy-α-methylbenzylamine

A solution of 14.0 g (92.0 mmol) of (R)-(-)- mandelic acid (Aldrich,99+%), 14.0 g (92.7 mmol) of (±) 3-methoxy-α-methylbenzylamine and 500mL of isopropanol was brought to reflux and gravity filtered while hot.The solution was then seeded at 50° C. with diastereomerically-pureseeds. After cooling to room temperature, the mixture was filtered toafford 10.9 g of a fluffy, white solid. This was recrystallized from 500mL of isopropanol. The solids were collected then partitioned betweenethyl acetate and saturated Na₂ CO₃. The organics were washed withsaturated NaCl, dried with Na₂ SO₄, and concentrated to afford 5.8 g(83%) of a yellow oil. NMR analysis of the derived camphorsulfonamide(FIG. 6) indicated that the chemical is enantiomerically pure, to thelimits of detection of NMR. This oil was distilled, b.p. 118°-120° C. ataspirator pressure, [α]_(D) =+3.8° (c+1 in 2N HCl). Preliminary resultssuggest that this compound may form a carbonate upon exposure to air. Itis therefore recommended that the chemical be stored under an inertatmosphere.

Example II

A. Imine formation:

A 100 ml round-bottomed flask equipped with magnetic stir bar, septurn,and nitrogen source, was charged with2-(2-chloro)-phenyl-1-ethanenitrile (4.996 g, 30.165 mole, ≈4.4 ml) indichloromethane (26 ml giving a total volume of≈30 ml, ≈1M in nitrile)and treated @ -78° C. with DIBAL-H (4.333 g, 30.467 mmol, 1.01 Eq.) at arate of 0.5 ml/min. After the addition, the reaction was removed fromthe -78° C. bath and stirred at room temperature for 60 min. After thistime, the reaction was cooled to -78° C. and treated with(R)-3'-methoxy-α-methylbenzylamine (4.555 g, 30.165 mmol, ≈4.4 ml)dropwise over 2 min. The reaction was stirred in the -78° C. bath andallowed to warm slowly to room temperature, where it remained overnight(20 hour reaction time after the addition of amine).

B. Reduction to Form Amine:

The reaction was then treated directly with sodium borohydride (1.2 g,31.72 mmol) followed by the slow addition of ethanol (10 ml) at a rateof 2 ml per hour. After the addition of ethanol, the reaction wasquenched with 10% HC1 (100 ml).

C. Separation and Analysis:

The acidic solution was basified (pH>12) by the addition of 10N NaOH andextracted with diethyl ether (300 ml). The ether layer was separated,dried over anhydrous MgSO₄, and concentrated to an oil. GC-EI-MSanalysis of this material showed a single component the product NPSR-568. TLC analysis (silica) with 3% (v/v) methanol in dichloromethaneshowed two UV active components at Rƒ 0.45 (product) and Rƒ 0.29.Spraying with ninhydrin (1° amines) and heating showed four additionalminor components at Rƒ 0.99, 0.51, 0.33, and 0.0. The component at Rƒ0.99 gave a true ninhydrin positive reaction. The components at Rƒ 0.99,0.45, 0.33, and 0.29 gave a positive response to Dragendorff's (2° and3° amines) reagent. One additional minor component was observed at Rƒ0.95 with iodoplatinate spray reagent (arnines). The reaction mixturewas chromatographed through silica (22×10 cm i.d.) using a gradient ofhexane to dichloromethane (containing 1% (v/v) isopropylamine) to 3%(v/v) methanol in dichloromethane (containing 1% (v/v) isopropylamine)to afford 6.990 g (76%) of the compound(R)-N-[1-(3-methoxyphenyl)ethyl]-3-(2-chlorobenzene)propanamine (alsoknown as N-[3-(2-chlorophenyl)propyl]-R-α-methyl-3-methoxybenzylamine orNPS R-568).

Example III

A. Diethyl o-Chlorobenzylmalonate

To a 50 liter flask, under argon atmosphere, was added ethyl alcohol(200 proof, 14.4 kg., 18,244 mL) and sodium metal (611.0 g, 26.58 mol).When the sodium metal has dissolved, the resulting solution was cooledto 15°±3° C. To this solution was added diethyl malonate (5.46 kg, 34.09mol) as rapidly as possible while maintaining the internal temperatureat 15°3° C. The reaction was allowed to stir for 30 minutes and was thencooled to 5°±5° C. To this solution was added 2-chlorobenzyl chloride(4.26 kg, 26.45 mol) at such a rate that the internal reactiontemperature was maintained at 5°±5° C. The reaction was allowed to stirat 5°±5° C. for two hours and then heated at reflux for one hour. Thereaction was then allowed to cool overnight with stirring.

The ethyl alcohol was removed in vacuo and ethyl acetate (11 L) wasadded to the residue. The organic phase was extracted with water (11 L),dried (Na₂ SO₄, 4 kg) and concentrated. The product was purified byvacuum distillation to give diethyl o-chlorobenzylmalonate (6102 g,81.2%, bp 161°-162° C. @ 0.3-0.4 mmHg) as a clear colorless liquid.

B. β-2-Chlorophenylpropionic Acid

To a 50 liter flask was added diethyl o-chlorobenzylmalonate (6067 g,21.31 mol), glacial acetic. acid (1090 mL), and concentratedhydrochloric acid (16,000 mL). The reaction was then heated at refluxfor 21 hours and 13 minutes. Additional concentrated hydrochloric acid(1840 mL, 5520 mL total) was added at 3.5, 13.5, and 17 hours into thereflux. The reaction was cooled to 0°±2° C. and the resulting solid wascollected by suction filtration and washed with water (4 L). The solidwas suspended in water (8 L) and the slurry was stirred for fiveminutes. The solid was collected by suction filtration and washed withwater (20 L). The filtrate was pH 2 and tested positive for chlorine.The solid was then washed seven times in the following manner; the solidwas suspended in water (8 L) and stirred for approximately ten minutes.The solid was collected by suction filtration and washed with water (4L). The filtrate was tested for chloride ion and the pH was recorded.The final filtrate was pH 4.5-5 and tested negative to the presence ofchloride ion. A total of 100 liters of water was used to wash the solid.The solid was dried under vacuum at 35°±3° C. for 70 hours to give crudeβ-2-chlorophenylpropionic acid (3653 g, 93.4%) as a white solid.

Crude β-2-chlorophenylpropionic acid (3644.7 g, 19.74 mol) was dissolvedin toluene (10.2 L) at 60°±10° C. The solution was cooled to 50°±10° C.and petroleum ether was added (35°-60° C., 23 L). The solution washeated until all of the solid dissolved. The solution was allowed tocool to room temperature and was then cooled to 0°±2° C. The resultingslurry was stirred at 0°±2° C. for two hours. The solid was collected bysuction filtration and washed with petroleum ether (35°-60° C., 5 L).The solid was dried under vacuum at 25°±2° C. for 25 hours to giveβ-2-chlorophenylpropionic acid (3348 g, 91.9%) as a white solid.

C. N-((R)-α-Methyl-3-methoxybenzyl)-3-(2-chlorobenzene)propanamide

To a solution of toluene (6000 mL) under argon atmosphere was addedβ-2-chlorophenylpropionic acid (2930.7 g, 15.87 mol) and(R)-3-methoxy-α-methylbenzylamine (2045.4 g, 13.53 mol). The reactionwas heated at reflux for 55 hours with azeotropic removal of water usinga Dean-Stark trap. The reaction was allowed to cool and was then dilutedwith ethyl acetate (21.3 kg, 23.6 L). The organic solution was extractedwith 10% hydrochloric acid (3×13.5 kg), 4% sodium hydroxide (3×13.5 kg)and brine (3×14 L). The organic phase was dried (Na₂ SO₄, 5 kg) andconcentrated in vacuo. The resulting solid was dried under vacuum at35°±2° C. for 22 hours to giveN-((R)-α-methyl-3-methoxybenzyl)-3-(2-chlorobenzene)propanamide (4023.3,93.8%) as a solid.

D. Reduction to form(R)-N-(3-methoxy-α-phenylethyl)-3-(2'-chlorophenyl)-1-propylamine HCl

To a 0°±5° C. solution of borane-tetrahydrofuran complex (1.0M, 17.94kg, 19,978 mL, 19.98 mol) in a 50 liter flask under argon atmosphere wasadded a solution ofN-((R)-α-methyl-3-methoxybenzyl)-3-(2-chlorobenzene)propanamide (3799.8g, 11.96 mol) dissolved in tetrahydrofuran (4700 mL). The addition tookplace over a period of one hour and nineteen minutes. The temperature ofthe reaction solution rose from 1° C. to 14° C. during the course of theaddition. With vigorous stirring, the reaction was heated to 68°±3° C.for two hours. The reaction was cooled to 3°±5° C. and a solution of 6Mhydrochloric acid (13,200 mL) was slowly added to the reaction.Tetrahydrofuran (18,100 mL) was removed from the reaction flask bydistillation at ambient pressure. Water (10 L) was added to the reactionflask and the solution was cooled to 0°±5° C. The resulting solid wascollected by suction filtration. The solid was washed with 5°±5° C.water (3×4000 mL) and dried under vacuum at 50°±5° C. for 98 hours togive crude(R)-N-(3-methoxy-α-phenylethyl)-3-(2'-chlorophenyl)-1-propylamine HCl(4630.2 g, 114.7%) as a white solid.

To a 22 liter flask was added crude(R)-N-(3-methoxy-α-phenylethyl)-3-(2'-chlorophenyl)-1-propylamine HCl(4626 g, 13.59 mol), ethyl alcohol (200 proof, 4280 mL), and water (4L). The solution was heated at reflux until all of the solid haddissolved. The hot solution was gravity filtered into a 50 liter flask.The 22 liter flask was rinsed with a solution of ethyl alcohol:water(1:1, 1000 mL) and filtered into the 50 liter flask. Water (31 L) wasadded to the filtered solution and the solution was heated until all ofthe solid dissolved. [Solid dissolved at 95° C.] The solution wasallowed to cool to room temperature and then was cooled to 0°±2° C. Theresulting slurry was stirred at 0°±2° C. for one hour. The solid wascollected by suction filtration, washed with 5°±5° C. water (4 L) anddried under vacuum at 50°±5° C. for 122 hours to give(R)-N-(3-methoxy-α-phenylethyl)-3-(2'-chlorophenyl)-1-propylamine HCl(3711.7 g, 92%) as a white solid.

Example IV

In a manner similar to the one described in Example II, exceptsubstituting the hereinafter-identified appropriate nitrile for2-(2-chloro)-phenyl-1-ethanenitrile and the hereinafter-identifiedappropriate amine for (R)-3'-methoxy-α-methylbenzylamine, the followingwere prepared: ##STR12## References herein to specific Examples orembodiments should not be interpreted as limitations to the invention'sscope, which is determined by the claims.

What is claimed is:
 1. The compound N-(R)-α-methyl-3-methoxybenzyl) -3-(2-chlorobenzene)propanamide. 